Abstract
Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death.
Highlights
Parkinson’s disease (PD) is the second most common neurological disorder characterized by motor and behavioral disturbances caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) [1]
In an attempt to study the role of endogenous Glycogen Synthase Kinase-3b (GSK-3b) in vivo in MPTP-induced dopaminergic neuronal cell death, we first examined the activation of Glycogen Synthase Kinase (GSK)-3b (i.e phosphorylation at tyrosine 216 residue (Tyr216) residue) in the SNc of MPTP-treated mice
The level of phospho-Tyr216-GSK-3b was significantly increased 7 days but not one day after the MPTP administration when compared to saline-treated controls (Figure 1B)
Summary
Parkinson’s disease (PD) is the second most common neurological disorder characterized by motor and behavioral disturbances caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) [1]. Inhibitors of complex I of the mitochondrial respiratory chain can produce the selective neuronal loss and consequent behavioral deficits mimicking PD hallmarks. In rodents, human and non-human primates, the neurotoxin 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) mediates selective damage to dopaminergic neurons of the nigro-striatal pathway [5]. Neuronal cell death is caused by MPP+, the active metabolite of MPTP, which induces oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP), the release of cytochrome c and the activation of caspases [6,7,8]. The mPTP results in increased permeability of the inner mitochondrial membrane to protons, ions and other solutes resulting in a decrease of the mitochondrial membrane potential (Dym)
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